The invention relates to an automatic chemical analyzer, and more particularly, to an improvement of such apparatus which performs the analysis of liquid sample such as blood or the determination of enzyme automatically.
Recently, there has been developed an automatic chemical analyzer which performs the analysis of liquid sample such as blood or urine or the determination of enzyme activity in an accurate, rapid and automatic manner. Such apparatus finds an extensive application in the field of clinical, chemical and pharmaceutical arts. The apparatus comprises means for injecting a liquid sample or reagent into a reaction tube, means which provides a colorimetric determination of the liquid after the chemical reaction or in the process thereof, and means for cleaning the tube with a flow of cleaning liquid through the tube after the reaction solution has been discharged from the tube upon completion of the determination. The apparatus is arranged to achieve an automatic analysis of a number of liquid samples to be examined in sequence in accordance with specified examining items.
While the reaction tube is maintained at a given temperature, for example, 37.degree. C., which is required for the determination, reagent or cleaning liquid which is injected into the tube assumes a normal temperature in the order of 10.degree. to 20.degree. C., and thus present a temperature differential with respect to the temperature which is optimally suited to the determination. Hence, their injection cools down the tube so that the desired temperature of 37.degree. C. cannot be reached for a considerable length of period at the commencement of the reaction between sample liquid and reagent. This cannot assure a reliable determination or analysis.
To avoid the foregoing problem, a chemical analyzer which heats the reagent and cleaning liquid to a given temperature before they are introduced into the reaction tube has been proposed. Such apparatus is illustrated in FIGS. 1 to 3. FIG. 1 shows a flow diagram. A liquid sample supply unit 101 includes a turntable 102, a plurality of sample tubes 103 disposed around the periphery thereof, and turntable drive 104. Liquid sample to be examined is contained in the individual sample tubes 103, and is withdrawn therefrom by sampling head 105 which comprises a suction tube 106 and an operator 107 which moves the suction tube.
The lower end of suction tube 106 is inserted into a sample tube which is held at a given position on the turntable 102, and sample liquid is withdrawn therefrom while it is maintained in this position. The suction tube can also be inserted into a cleaning vessel 108, as indicated in broken lines. When it is so inserted, water, for example, may be sprayed from nozzle 109 to clean the lower end of the suction tube. Sample liquid which has been withdrawn from the sample tubes 103 is introduced into a metering valve 110, which comprises a pair of stationary members 111, 112 and a rotating member 113 which is interposed therebetween in a manner to maintain a close contact therewith. The rotating member 113 is formed with at least two openings 114a, 114b which are of an equal volume. Stationary member 111 is connected with sampling head 105 while stationary member 112 is connected with directional control valve 115, which is in turn connected with pump 116. Pump 116 is connected with vessel 117, which contains a cleaning liquid, through valve 115. In the solid line position of valve 115, liquid sample to be examined is withdrawn from sample tube 103 by means of pump 116 and is introduced into the opening 114a formed in metering valve 110. In the broken line position of valve 115, cleaning liquid 118 contained within vessel 117 is withdrawn and is passed through metering valve 110 to be discharged into vessel 108, thus cleaning the internal passage of various parts to which the sample liquid may remain attached. Rotary reactor 119 comprises rotating body 120, and a plurality of reaction tubes 121 which are disposed on and held by rotating body 120 on a common circumference thereof. Rotating body 120 is intermittently driven for rotation by an associated drive. Characters A.sub.O, B.sub.O, C.sub.O . . . L.sub.O represent various positions where reaction tubes 121 remain stationary. Valves 145, 146 (see FIG. 2) are disposed on top of and beneath reactor 119. Rotating body 120 is centrally provided with light source 122, and detector 123 is disposed in opposing relationship therewith.
FIG. 2 shows the detail of reactor 119. In this Figure, a pair of vertically spaced partition plates 124, 125 define an air bath which maintains, by way of example, a constant temperature of 37.degree. C. Pipe 126 extends through the plates and has its upper end secured to fixture 127 and its lower end to fixtures 128 and 129, whereby it is fixedly mounted on partition plates 124, 125. Collar 130 is fitted over pipe 126 in position thereon, and rotating body 120 is disposed around collar 130 and is rotatably supported by bearings 131, 132.
A plurality of reaction tubes 121 (twelve in the present example), are mounted on a common circle of rotating body 120. Individual reaction tubes are formed of a material such as fused quartz which exhibits a chemical resistance, and is made transparent in at least its region where light is intended to be passed therethrough. Light passages 133 are formed in rotating body 120 in the region of individual reaction tubes. An opening 134 is formed in a collar 130 and pipe 126 at a given position thereof so that light reflected by reflecting mirror 135, which is secured in the central portion of pipe 126, can be passed through opening 134 and passage 133 to irradiate a reaction tube 121. The transmitting light is detected by detector 123 which is disposed within shielded casing 136. Lamp protecting casing 139 is fixedly mounted on top of fixture 127 and contains lamp 122, condenser lens 137 and filter 138. Light from the lamp is collimated by the lens and is directed through pipe 126 onto reflecting mirror 135.
Rotating body 120 is peripherally formed with Geneva gear 140 having a number of teeth which is a multiple of the number of reaction tubes 121. In the present embodiment, it has 24 teeth. Geneva gear is intermittently engaged by pin 142 fixedly mounted on eccentric plate 141, which is fixedly mounted on shaft 143 that extends through and is supported by the upper partition plate 124. Gear 143a is secured to the upper end of the shaft and is operatively connected with drive 144 such as motor which is fixedly mounted on partition plate 124. By operating drive 144 in a programmed manner, it is possible to rotate Geneva gear by an amount corresponding to two teeth with one revolution of pin 142 about shaft 143, thus intermittently rotating body 120 and hence reaction tubes 121. Valves 145, 146 comprise stationary blocks 147, 149 and rotating blocks 148, 150. Stationary block 147 of upper valve 145 is secured to fixture 127 while rotating block 148 is fixedly mounted on rotating body 120 by means of holder 151. Stationary block 149 of lower valve 146 is secured to pipe 126 by means of holder 152 while its rotating block 150 is secured to the bottom of rotating body 120 by means of holder 153. Rotating blocks 148, 150 are formed with a number of flow passages 154, 155 which are equal in number to the number of reaction tubes 121 and which communicate with the latter through thin pipes 156. Those stationary blocks which are located at positions corresponding to the introduction and discharge or drain of sample, reagent, cleaning liquid or air are formed with passages 157, 158 which communicate through pipes 159, 159' with means which supply or drain liquid, introduce air or apply suction.
Returning to FIG. 1, position A.sub.O of reaction tube 121 represents a first position where sample and first reagent are introduced into a reaction tube. In this position, lower valve 146 of FIG. 2 is connected with stationary member 112 of liquid sample metering valve 110. Stationary member 111 of metering valve 110 is connected with line 161 which extends through preheater 160. Pump 162 is disposed in line 161, which has its lower end inserted into vessel 164 which is filled with first reagent 163.
The detailed construction of preheater 160 is shown in FIG. 3. As shown, preheater 160 represents an enclosed housing which is filled with liquid such as oil or water or gas. It internally houses heating element 166 which is connected with power source 165 for purpose of heating the liquid. Fan 167 is disposed in the bottom of the enclosed housing and is maintained in rotation by motor 168 to agitate the liquid contained in the interior of the housing to achieve a uniform temperature throughout the liquid. Temperature sensor 169 is located at a suitable position within the housing, and produces a temperature signal which is fed to control circuit 170 in order to control power source 165 so that the liquid temperature may be maintained substantially constant at 37.degree. C., for example. Part of line 161 which is connected with metering valve 110 and pump 162 extends through the preheater housing, and is formed in zig-zag or helical form therein to enhance the thermal efficiency of heating the reagent to the given temperature. Lines 171 and 172 of a similar configuration as line 161 also extend through the preheater housing. Line 171 is used to supply second reagent while line 172 is used to supply cleaning liquid.
When pump 162 is set in motion, first reagent 163 is withdrawn, heated to the given temperature within preheater 160 and is introduced into metering valve 110. A fraction of sample liquid which is metered by the opening 114b of a given volume that is formed in rotating member 13 is displaced therefrom and fed through pipe 159' and lower valve 146 into the reaction tube 121 which is located at the position A.sub.O. Means for agitating the sample and first reagent is located intermediate the positions A.sub.O and B.sub.O. Specifically, in such a region, lower valve 146 is connected through pipe 159' with resistive tube 173 while upper valve 145 is connected with vacuum pump 176 through pipe 159, line 174 and reservoir 175. The top region of the reaction tube is reduced in pressure while air or any other desired gas is introduced into the bottom region thereof through tube 173. Air bubbles through the liquid upwardly, whereby the sample liquid and first reagent which have been introduced into the reaction tube at position A.sub.O are sufficiently agitated to accelerate the reaction therebetween.
Position H.sub.O represents the reaction tube position where the second reagent is introduced. At this position, lower valve 146 is connected through pipe 159' and line 171 with pump 177, and has its end inserted into vessel 179 which is filled with second reagent 178. The operation of a pump 177 withdraws second reagent, which is then heated to a given temperature by passing through preheater 160, and thereafter introduced into a corresponding reaction tube 121 through lower valve 146. Agitation means is similarly disposed intermediate positions H.sub.O and I.sub.O. Air is introduced through resistive tube 180 and lower valve 146 to produce bubbles which achieves an agitation of second reagent with the sample which has terminated the reaction with or is in the process of reaction with first reagent. Position J.sub.O represents a determining position where light from lamp 122 is passed through the correspondingly located reaction tube to irradiate the reaction solution and the resulting transmitting light is detected by detector 123. An output signal from the detector is applied to amplifier 181 and thence to a recorder or display 182, thus plotting the light absorbance against the time axis. Part of the output signal from amplifier 181 is also fed to A-D converter 183 to be converted into a digital signal, which may be fed to data analyzer 184 such as an electronic computer, for example, to effect a desired calculation. The calculated result, for example, the enzyme activity is displayed after each determination or in a desired manner.
Positions K.sub.O and L.sub.O each represent a cleaning position where a cleaning liquid such as water which is heated to a given temperature is introduced through lower valve 146, pipe 159' and line 172. Line 172 is connected with vessel 117 through air mixer 185 and pump 186. Compressed air is supplied from compressor 187 to air mixer 185 through valve 188 to admix air with cleaning liquid supplied from pump 186. As a consequence, cleaning liquid which contains bubbles is introduced into reaction tube 121, thus enhancing the cleaning effect. Between positions J.sub.O and K.sub.O, between positions K.sub.O and L.sub.O and between positions L.sub.O and A.sub.O where the liquid content within a reaction tube is to be discharged or drained, compressed air is introduced into the top of the reaction tube from compressor 187 through valve 189, line 190, pipe 159 and upper valve 145, thus pneumatically displacing the liquid from the reaction tube through lower valve 146, pipe 159' and line 191 and thence to a drainage sump (not shown).
With the described arrangement, reagent is heated within preheater 160 to a temperature which is substantially the same as that of the reactor before it is fed into reaction tubes, so that the reaction solution is maintained at a given temperature during the reaction and during the determination, thus permitting an accurate colorimetric determination.
However it will be understood that the resulting arrangement is complicated and bulky in size since the air bath defined by partition plates 124, 125, and which maintains a constant temperature therein, must house a number of parts including rotating body 120, reaction tubes 121 fixedly mounted thereon, valves 145, 146 which supply sample liquid, first and second reagent and cleaning liquid into the reaction tubes, reflecting mirror 135, detector 123 and intermittent drive associated with rotating body 120. Because the reaction tubes are completely secured to the rotating body, it is difficult to replace them. Additionally, in the event of a failure of valves, they cannot be repaired without disassembling the arrangement. A more significant disadvantage is the fact that valves, reflecting mirror, detector and intermittent drive which need not be maintained at a constant temperature are also assembled into the air bath, thus requiring an increased and wasteful heat capacity of the air bath. It will be appreciated that the maintenance of a constant temperature is required only for the reaction tubes and various liquids which are injected therein while valves, reflecting mirror, detector and intermittent drive need not be maintained at a constant temperature. It is also appreciated that it is only necessary that the chemical reaction solution comprising a mixture of sample liquid to be examined and reagent or reagents be maintained at a given temperature (for example, 37.degree. C.) at the colorimetric determining position to assure a proper chemical reaction, but need not be closely controlled to such temperature at other positions.